Prostaglandin EP1 receptor down-regulates expression of cyclooxygenase-2 by facilitating its proteasomal degradation |
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Authors: | Haddad Ariz Flint-Ashtamker Galit Minzel Waleed Sood Rapita Rimon Gilad Barki-Harrington Liza |
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Institution: | Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Mt. Carmel, Haifa 31905, Israel. |
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Abstract: | The enzyme cyclooxygenase-2 (COX-2) is rapidly and transiently up-regulated by a large variety of signals and implicated in pathologies such as inflammation and tumorigenesis. Although many signals cause COX-2 up-regulation, much less is known about mechanisms that actively down-regulate its expression. Here we show that the G protein-coupled receptor prostaglandin E(1) (EP(1)) reduces the expression of COX-2 in a concentration-dependent manner through a mechanism that does not require receptor activation. The reduction in COX-2 protein is not due to decreased protein synthesis and occurs because of enhancement of substrate-independent COX-2 proteolysis. Although EP(1) does not interfere with the entry of COX-2 into the endoplasmic reticulum-associated degradation cascade, it facilitates COX-2 ubiquitination through complex formation. Blockade of proteasomal activity results in degradation of the receptor and concomitant recovery in the expression of COX-2, suggesting that EP(1) may scaffold an unknown E3 ligase that ubiquitinates COX-2. These findings propose a new role for the EP(1) receptor in resolving inflammation through down-regulation of COX-2. |
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Keywords: | Cell Surface Receptor Cyclooxygenase (COX) Pathway Enzyme Degradation G Protein-coupled Receptors (GPCR) Ubiquitination |
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